P1399: INITIAL CLINICAL RESULTS OF EUPLAGIA-1, A PHASE 1/2 TRIAL OF POINT-OF-CARE MANUFACTURED GLPG5201 IN R/R CLL/SLL WITH OR WITHOUT RICHTER’S TRANSFORMATION
Authors: Nuria Martinez-Cibrian, Sergi Betriu, Valentín Ortiz-Maldonado, Daniel Esteban, Natalia Tovar, Ana Triguero Moreno, Leticia Alserawan, Mercedes Montoro, Anna Van Muyden, Maike Spoon, Margot Pont, Christian Jacques, Julio Delgado
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) remain incurable, despite advances in treatment. Moreover, patients (pts) with Richter's transformation (RT) have a poor prognosis with limited treatment options. CD19-directed CAR-T therapy improved survival for pts with a broad range of B-cell malignancies. Clinical trials of CD19 CAR-Ts have shown promising antitumor responses in CLL and SLL, with or without RT. However, no CAR-T cell therapies have been approved for these pt populations. A standardized, decentralized point‑of-care (PoC) manufacturing workflow was established with Lonza's Cocoon™ Platform, enabling clinicians to administer autologous CAR-T treatments within 7 days of apheresis. This fully automated workflow eliminates complex logistics or cryopreservation, improving product attributes and significantly decreasing the vein-to-vein time. This could overcome major limitations of currently available CAR-Ts. Aims: To evaluate the feasibility, safety and efficacy of PoC-manufactured GLPG5201 in pts with relapsed/refractory (R/R) CLL and SLL, with or without RT. Methods: Euplagia-1/CP0101-CLL (EudraCT 2021-003815-25) is a Phase (Ph) 1/2 study evaluating the feasibility, safety and efficacy of PoC-manufactured GLPG5201 in pts with R/R CLL and SLL. GLPG5201 is a 2nd generation anti-CD19/4-1BB CAR-T product, administered as a fresh product in a single fixed dose. Pts with CD19+ R/R CLL or R/R SLL with ≥2 lines of therapy are eligible. Pts with RT are eligible regardless of prior therapy. Three dose levels are planned: 35×106 (DL1), 100×106 (DL2) and 300×106 (DL3) CAR+ viable T cells. The study uses a Bayesian Optimal Interval design (n=15 pts) for Ph 1. The Ph 1 endpoints are safety and establishing a recommended dose for Ph 2. Following screening and enrollment, pts will receive daily ibrutinib continuously until mononuclear cell leukapheresis. During GLPG5201 manufacturing, pts receive cyclophosphamide (300 mg/m2/day)/fludarabine (30 mg/m2/day) for 3 days. After a resting period of at least 2 days, GLPG5201 is freshly administered in a single intravenous infusion. All pts remain hospitalized for at least 7 days; end-of-treatment visit is at Week 14 post–CAR-T infusion. Results: Seven pts have been enrolled in the ongoing Ph 1 study at the time of analysis (data cut-off 9 January 2023). The median age is 66 y (58–71 y); 5/7 are male. All 7 pts were diagnosed with R/R CLL; 4/7 pts had RT. All pts received GLPG5201 as a fresh infusion at DL1 (n=4) or at DL2 (n=3); median vein-to-vein time was 7 days. No dose-limiting toxicities were reported for DL1 or DL2. Most adverse events were grade 1–2 (mostly hematological; Table 1). No grade 3 or 4 cytokine release syndrome or any-grade neurotoxicity was observed. All enrolled pts responded to treatment (overall response rate [ORR]: 100%); 6/7 pts reached a complete response (complete response rate: 86%). One pt (DL1) progressed after an initial partial response and had a CD19-negative relapse with confirmed RT. Responses have been recorded up to 7 months; follow-up is ongoing. High peak expansion levels and prolonged CAR-T cell persistence were observed in the peripheral blood. Summary/Conclusion: GLPG5201 is a new CAR-T therapeutic option for pts with R/R CLL with or without RT, showing limited toxicity and promising efficacy based on current results (n=7). For all 7 pts, GLPG5201 was successfully manufactured at the PoC and administered as a fresh product, with a median vein-to-vein time of 7 days. Rapid complete responses have been observed with a 100% ORR in a heavily pre-treated pt population. Ph 1 recruitment is ongoing to establish a recommended dose for Ph 2.Keywords: Chronic lymphocytic leukemia, Immunotherapy, Cellular therapy, CAR-T